Interaction of ABC Multidrug Transporters with Anticancer Protein Kinase Inhibitors: Substrates and/or Inhibitors?

Csilla      Ozvegy-Laczka; Csilla      Hegedus; Gergely      Szakacs; Balazs      Sarkadi

doi:10.2174/156800909788166565

Abstract

Protein kinase inhibitors (PKI) are becoming key agents in modern cancer chemotherapy, and combination of PKIs with classical chemotherapeutic drugs may help to overcome currently untreatable metastatic cancers. Since chemotherapy resistance is a recurrent problem, mechanisms of resistance should be clarified in order to help further drug development. Here we suggest that in addition to PKI resistance based on altered target structures, the active removal of these therapeutic agents by the MDR-ABC transporters should also be considered as a major cause of clinical resistance. We discuss the occurring systemic and cellular mechanisms, which may hamper PKI efficiency, and document the role of selected MDR-ABC transporters in these phenomena through their interactions with these anticancer agents. Moreover, we suggest that PKI interactions with ABC transporters may modulate overall drug metabolism, including the fate of diverse, chemically or target-wise unrelated drugs. These effects are based on multiple forms of MDR-ABC transporter interaction with PKIs, as these compounds may be both substrates and/or inhibitors of an ABC transporter. We propose that these interactions should be carefully considered in clinical application, and a combined MDR-ABC transporter and PKI effect may bring a major advantage in future drug development.

Keywords: Multidrug resistance, MDR-ABC transporters, MDR1-Pgp, MRP1, ABCG2, Small molecule protein kinase inhibitors, Tyrosine kinases, Receptor tyrosine kinases